Ferritin nanovehicle for targeted delivery of cytochrome C to cancer cells

In this work, we have exploited the unique properties of a chimeric archaeal-human ferritin to encapsulate, deliver and release cytochrome c and induce apoptosis in a myeloid leukemia cell line. The chimeric protein combines the versatility in 24-meric assembly and cargo incorporation capability of Archaeglobus fulgidus ferritin with specific binding of human H ferritin to CD71, the “heavy duty” carrier responsible for transferrin-iron uptake. Delivery of ferritin-encapsulated cytochrome C to the Acute Promyelocytic Leukemia (APL) NB4 cell line, highly resistant to transfection by conventional methods, was successfully achieved in vitro. The effective liberation of cytochrome C within the cytosolic environment, demonstrated by double fluorescent labelling, induced apoptosis in the cancer cells

Exploring the use of dimethyl fumarate as microglia modulator for neurodegenerative diseases treatment

The maintenance of redox homeostasis in the brain is critical for the prevention of the development of neurodegenerative diseases. Drugs acting on brain redox balance can be promising for the treatment of neurodegeneration. For more than four decades, dimethyl fumarate (DMF) and other derivatives of fumaric acid ester compounds have been shown to mitigate a number of pathological mechanisms associated with psoriasis and relapsing forms of multiple sclerosis (MS). Recently, DMF has been shown to exert a neuroprotective effect on the central nervous system (CNS), possibly through the modulation of microglia detrimental actions, observed also in multiple brain injuries. In addition to the hypothesis that DMF is linked to the activation of NRF2 and NF-kB transcription factors, the neuroprotective action of DMF may be mediated by the activation of the glutathione (GSH) antioxidant pathway and the regulation of brain iron homeostasis. This review will focus on the role of DMF as an antioxidant modulator in microglia processes and on its mechanisms of action in the modulation of different pathways to attenuate neurodegenerative disease progression

Comprehensive track-structure based evaluation of DNA damage by light ions from radiotherapy- relevant energies down to stopping

Track structures and resulting DNA damage in human cells have been simulated for hydrogen, helium, carbon, nitrogen, oxygen and neon ions with 0.25–256 MeV/u energy. The needed ion interaction cross sections have been scaled from those of hydrogen; Barkas scaling formula has been refined, extending its applicability down to about 10 keV/u, and validated against established stopping power data. Linear energy transfer (LET) has been scored from energy deposits in a cell nucleus; for very low-energy ions, it has been defined locally within thin slabs. The simulations show that protons and helium ions induce more DNA damage than heavier ions do at the same LET. With increasing LET, less DNA strand breaks are formed per unit dose, but due to their clustering the yields of double-strand breaks (DSB) increase, up to saturation around 300 keV/μm. Also individual DSB tend to cluster; DSB clusters peak around 500 keV/μm, while DSB multiplicities per cluster steadily increase with LET. Remarkably similar to patterns known from cell survival studies, LET-dependencies with pronounced maxima around 100– 200 keV/μm occur on nanometre scale for sites that contain one or more DSB, and on micrometre scale for megabasepair-sized DNA fragments

A novel strategy for molecular interfaces optimization: the case of ferritin-transferrin receptor interaction

Protein-protein interactions regulate almost all cellular functions and rely on a fine tune of surface amino acids properties involved on both molecular partners. The disruption of a molecular association can be caused even by a single residue mutation, often leading to a pathological modification of a biochemical pathway. Therefore the evaluation of the effects of amino acid substitutions on binding, and the ad hoc design of protein-protein interfaces, is one of the biggest challenges in computational biology. Here, we present a novel strategy for computational mutation and optimization of protein-protein interfaces. Modeling the interaction surface properties using the Zernike polynomials, we describe the shape and electrostatics of binding sites with an ordered set of descriptors, making possible the evaluation of complementarity between interacting surfaces. With a Monte Carlo approach, we obtain protein mutants with controlled molecular complementarities. Applying this strategy to the relevant case of the interaction between Ferritin and Transferrin Receptor, we obtain a set of Ferritin mutants with increased or decreased complementarity. The extensive molecular dynamics validation of the method results confirms its efficacy, showing that this strategy represents a very promising approach in designing correct molecular interfaces

A gold-containing drug against parasitic polyamine metabolism: the X-ray structure of trypanothione reductase from Leishmania infantum in complex with auranofin reveals a dual mechanism of enzyme inhibition

Auranofin is a gold(I)-containing drug in clinical use as an antiarthritic agent. Recent studies showed that auranofin manifests interesting antiparasitic actions very likely arising from inhibition of parasitic enzymes involved in the control of the redox metabolism. Trypanothione reductase is a key enzyme of Leishmania infantum polyamine-dependent redox metabolism, and a validated target for antileishmanial drugs. As trypanothione reductase contains a dithiol motif at its active site and gold(I) compounds are known to be highly thiophilic, we explored whether auranofin might behave as an effective enzyme inhibitor and as a potential antileishmanial agent. Notably, enzymatic assays revealed that auranofin causes indeed a pronounced enzyme inhibition. To gain a deeper insight into the molecular basis of enzyme inhibition, crystals of the auranofin-bound enzyme, in the presence of NADPH, were prepared, and the X-ray crystal structure of the auranofin–trypanothione reductase–NADPH complex was solved at 3.5 Å resolution. In spite of the rather low resolution, these data were of sufficient quality as to identify the presence of the gold center and of the thiosugar of auranofin, and to locate them within the overall protein structure. Gold binds to the two active site cysteine residues of TR, i.e. Cys52 and Cys57, while the thiosugar moiety of auranofin binds to the trypanothione binding site; thus auranofin appears to inhibit TR through a dual mechanism. Auranofin kills the promastigote stage of L. infantum at micromolar concentration; these findings will contribute to the design of new drugs against leishmaniasis

IENE 9 project: developing a culturally competent and compassionate LGBT + curriculum in health and social care education

Introduction The IENE projects (2008–2022) aim to promote a model for developing intercultural dialogue and enhance the ability to provide culturally competent and compassionate care for the health and social care professionals at national and European levels. The IENE 9 project, named “Developing a culturally competent and compassionate LGBT + curriculum in health and social care education,” builds on the work developed in the previous IENE projects and emphasizes the importance of addressing LGBT + issues in health and social care education. Method Through an innovative Massive Open Online Course (MOOC), professionals will learn the skills to work toward building an LGBT + inclusive health and social care system. Result Notwithstanding the progress made in recent years on LGBT + issues, research indicates that too little attention has been given to LGBT + needs in health and social care settings, and these remain substantial issues that are often ignored. Conclusion This letter to the editor aims to present the IENE 9 project given that greater efforts are needed to improve professionals’ skills regarding sexual and gender minority population. We strive to continue our efforts in promoting the well-being and mental health of LGBT + people in health and social care education

GARFIELD + RCo Digital Upgrade: a Modern Set-up for Mass and Charge Identification of Heavy Ion Reaction Products

An upgraded GARFIELD + Ring Counter (RCo) apparatus is presented with improved performances as far as electronics and detectors are concerned. On one side fast sampling digital read out has been extended to all detectors, allowing for an important simplification of the signal processing chain together with an enriched extracted information. On the other side a relevant improvement has been made in the forward part of the setup (RCo): an increased granularity of the CsI(Tl) crystals and a higher homogeneity in the silicon detector resistivity. The renewed performances of the GARFIELD + RCo array make it suitable for nuclear reaction measurements both with stable and with Radioactive Ion Beams (RIB), like the ones foreseen for the SPES facility, where the Physics of Isospin can be studied.Comment: 13 pages, 19 figures - paper submitted to Eur. Phys. J.

What factors might drive Voluntary Childlessness (VC) in women with IBD? Does IBD-specific pregnancy-related knowledge matter?

Introduction: Inflammatory Bowel Disease (IBD) affects many women of child bearing age and rates of voluntary childlessness (VC) exceed those of the general population by far. The factors surrounding VC remain incompletely understood. Methods: Female members of the patient organisation Crohn’s and Colitis UK aged 18-45 years were invited to complete an online questionnaire collecting data on demographics, disease characteristics, pregnancy specific disease-related knowledge (CCPKnow) and childlessness status. Results: 1324 women (mean age 33 years) completed the survey. 776 (59%) were diagnosed with from Crohn’s disease (CD), 496 (38%) with ulcerative colitis (UC) and 4% with IBD-U. 40% had children (14% pre-diagnosis (I); 26% post-diagnosis (II)), 36% planned to have children at some stage (III), 7% reported fertility problems (IV) and 17% were classified as voluntarily childless (VC). VC was associated with poorer CCPKnow scores (5.98 vs 7.47 in (III); p<0.001), older age (35y vs 28y in (II); p<0.001), unemployment (9.7% VC; p<0.001), being single (34.5% VC; p<0.001, not seeking medical advice (p<0.001), and diagnosis of CD (19.3% vs 13.9% UC; p=0.015). Women with VC had more hospital admissions (mean 2.85 vs 2.17 (III); p=0.03) and surgical interventions (mean 1.27 vs 0.65 (III); p<0.001). Conclusion: The aetiology of VC in women with IBD is multifactorial. Women’s choice regarding children appears related to disease burden. VC is also associated with poor knowledge (CCPKnow) and women may stay childless unnecessarily. Patient education programmes could help to reduce the rate of VC in women with IBD through correcting misconceptions and alleviating patient concerns

LGBT+ Training needs for health and social care professionals: a cross-cultural comparison among seven European countries

Introduction Research suggests that specific training on LGBT+ issues may improve the competencies and skills of health and social care (HSC) professionals, which reduces the negative attitudes toward LGBT+ people. Despite this, there seems to be a lack of coverage of LGBT+ needs in HSC education. The present study aims to explore the specific LGBT+ training needs of HSC professionals and to examine the relationship between these training needs and the four dimensions of the Papadopoulos model, i.e. cultural awareness, cultural knowledge, cultural sensitivity, and cultural competence. Methods The research used data from a cross-cultural project, “Intercultural Education for Nurses in Europe (IENE9),” which was administered to 412 HSC academics and workers (62% females; Mage=46.06, SDage=10.48) between February 2020 and July 2020, in seven European countries: UK (coordinator), Denmark, Spain, Germany, Cyprus, Italy, and Romania. Results Hierarchical multiple regression showed that higher training needs were associated with cultural awareness, cultural knowledge, and cultural competence. The need for training on LGBT+ issues was higher for Cyprus, Romania, Spain, Italy, and the UK, compared with Denmark (no differences between Germany and Denmark were found). Conclusions We believe that there has been a lack of focus on the LGBT+ training needs of HSC professionals: Greater efforts are required to develop a culturally competent and compassionate LGBT+ curriculum. Social Policy Implications Findings from the present study will inform the development of a free, Massive Open Online Course (MOOC), for culturally competent and compassionate HSC professionals in Europe to improve the quality of their car